Risk taking behavior is strongly associated with drug use; however, the nature of the relationship between risk taking and drug use is not well established. The overall goal of this proposal is to use a rat model to determine a) potential bidirectional relationships between risk taking and drug use, and b) the role of dopamine signaling in mediating these relationships. In particular, experiments in this proposal will focus on risk taking during adolescence, as some studies in humans have associated risky behavior during this period with increased likelihood of future drug use. Risk taking will be assessed in adolescent rats using the Risky Decision-making Task, in which rats choose between small safe rewards and large risky rewards that are accompanied by varying risks of punishment (this task is a model of conditions in which highly rewarding choices are accompanied by risks of adverse consequences). This type of decision making is highly relevant to the issue of adolescent risk taking and drug use, as both adolescents and drug users are prone to poor decision-making and often fail to adequately assess and/or act on the potential for adverse outcomes. Experiments under Aim 1 will determine whether individual differences in adolescent risk taking predict cocaine self-administration during adulthood. Aim 1 will also investigate whether chronic cocaine self-administration in adulthood causes lasting increases in risky decision-making (thus resulting in a vicious circle of risky behavior and drug use). Experiments under Aims 2 and 3 will investigate the role of dopamine signaling in mediating the relationship between adolescent risk taking and cocaine use, with particular focus on D2-like receptors and the dopamine transporter, which have been linked to both risk taking and cocaine use in preliminary and previously published data. Specifically, Aim 2 will use in situ hybridization to determine the relationship between both adolescent risk taking and chronic cocaine's effects on risk taking, and expression of mRNA for D2, D3, and D4 receptors, as well as the dopamine transporter, with a particular focus on the striatum. Experiments under Aim 3 will test the functional relevance of relationships identified in the preliminary data and Aim 2 between risky decision-making and dopaminergic markers, using intracerebral microinjections of drugs targeting these markers in brain regions of interest such as dorsal striatum. Results from this research will provide insight into the direction(s) of causality in the relationship between risk taking behavior and drug use, as well as the dopaminergic regulation of risky decision-making. Such information may be useful from clinical, epidemiological, and social policy perspectives for developing strategies to treat and prevent drug use. PUBLIC HEALTH RELEVANCE: Both adolescents and drug users are prone to engage in risky behavior, which may increase propensity to initiate and relapse to drug use; however, the nature of the relationships between adolescent risk taking and drug use is not well established. The proposed research will use an animal model to investigate these relationships at both the behavioral and neurobiological levels, which could aid in the development of novel addiction treatments.